Modeling human endometrial decidualization from the interaction between proteome and secretome

CONTEXT: Decidualization of the human endometrium, which involves morphological and biochemical modifications of the endometrial stromal cells (ESCs), is a prerequisite for adequate trophoblast invasion and placenta formation. OBJECTIVE: This study aims to investigate the proteome and secretome of in vitro decidualized ESCs. These data were combined with published genomic information and integrated to model the human decidualization interactome. DESIGN: Prospective experimental case-control study. SETTING: A private research foundation. PATIENTS: Sixteen healthy volunteer ovum donors. INTERVENTION: Endometrial samples were obtained, and ESCs were isolated and decidualized in vitro. MAIN OUTCOME MEASURES: Two-dimensional difference in-gel electrophoresis, matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry, Western blot, human protein cytokine array, ELISA, and bioinformatics analysis were performed. RESULTS: The proteomic analysis revealed 60 differentially expressed proteins (36 over- and 24 underexpressed) in decidualized versus control ESCs, including known decidualization markers (cathepsin B) and new biomarkers (transglutaminase 2, peroxiredoxin 4, and the ACTB protein). In the secretomic analysis, a total of 13 secreted proteins (11 up- and 2 down-regulated) were identified, including well-recognized markers (IGF binding protein-1 and prolactin) and novel ones (myeloid progenitor inhibitory factor-1 and platelet endothelial cell adhesion molecule-1). These proteome/secretome profiles have been integrated into a decidualization interactome model. CONCLUSIONS: Proteomic and secretomic have been used as hypothesis-free approaches together with complex bioinformatics to model the human decidual interactome for the first time. We confirm previous knowledge, describe new molecules, and we have built up a model for human in vitro decidualization as invaluable tool for the diagnosis, therapy, and interpretation of biological phenomena.The participation of T.G.-G. was supported by a grant of the Ministry of Education and Science AP2007-04066 (FPU). CNIC was supported by the Spanish Ministry of Science and Innovation and the Pro-CNIC Foundation.S

The Sustainable Development Goals and Aerospace Engineering: A critical note through Artificial Intelligence

The 2030 Agenda of the United Nations (UN) revolves around the Sustainable Development Goals (SDGs). A critical step towards that objective is identifying whether scientific production aligns with the SDGs' achievement. To assess this, funders and research managers need to manually estimate the impact of their funding agenda on the SDGs, focusing on accuracy, scalability, and objectiveness. With this objective in mind, in this work, we develop ASDG, an easy-to-use Artificial-Intelligence-based model for automatically identifying the potential impact of scientific papers on the UN SDGs. As a demonstrator of ASDG, we analyze the alignment of recent aerospace publications with the SDGs. The Aerospace data set analyzed in this paper consists of approximately 820,000 papers published in English from 2011 to 2020 and indexed in the Scopus database. The most-contributed SDGs are 7 (on clean energy), 9 (on industry), 11 (on sustainable cities), and 13 (on climate action). The establishment of the SDGs by the UN in the middle of the 2010 decade did not significantly affect the data. However, we find clear discrepancies among countries, likely indicative of different priorities. Also, different trends can be seen in the most and least cited papers, with apparent differences in some SDGs. Finally, the number of abstracts the code cannot identify decreases with time, possibly showing the scientific community's awareness of SDG.RV and FFN acknowledge the support of the KTH Climate Action Centre and Digital Futures. SHC is partially funded by project PID2021-128676OB-I00 by Ministerio de Ciencia, innovación y Universidades / FEDER

Von Hippel-Lindau protein is required for optimal alveolar macrophage terminal differentiation, self-renewal, and function

The rapid transit from hypoxia to normoxia in the lung that follows the first breath in newborn mice coincides with alveolar macrophage (AM) differentiation. However, whether sensing of oxygen affects AM maturation and function has not been previously explored. We have generated mice whose AMs show a deficient ability to sense oxygen after birth by deleting Vhl, a negative regulator of HIF transcription factors, in the CD11c compartment (CD11c Delta Vhl mice). VHL-deficient AMs show an immature-like phenotype and an impaired self-renewal capacity in vivo that persists upon culture ex vivo. VHL-deficient phenotype is intrinsic in AMs derived from monocyte precursors in mixed bone marrow chimeras. Moreover, unlike control Vhl(fl/fl), AMs from CD11c Delta Vhl mice do not reverse pulmonary alveolar proteinosis when transplanted into Csf2rb(-/)(-) mice, demonstrating that VHL contributes to AM-mediated surfactant clearance. Thus, our results suggest that optimal AM terminal differentiation, self-renewal, and homeostatic function requires their intact oxygen-sensing capacity

Feature extraction and similarity of movement detection during sleep, based on higher order spectra and entropy of the actigraphy signal: Results of the Hispanic Community Health Study/Study of Latinos

[EN] The aim of this work was to develop a new unsupervised exploratory method of characterizing feature extraction and detecting similarity of movement during sleep through actigraphy signals. We here propose some algorithms, based on signal bispectrum and bispectral entropy, to determine the unique features of independent actigraphy signals. Experiments were carried out on 20 randomly chosen actigraphy samples of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) database, with no information other than their aperiodicity. The Pearson correlation coefficient matrix and the histogram correlation matrix were computed to study the similarity of movements during sleep. The results obtained allowed us to explore the connections between certain sleep actigraphy patterns and certain pathologies.Funding for this study was provided by the authors' departments. J.A.C. acknowledges support from the Ministerio de Economia, Industria y Competitividad, Grant MTM2016-75963-P. J.M.G.-G. y C.S. Ministerio de Ciencia Tecnologia y Telecomunicaciones, Grant DPI2016-80054-R. J.A.C., J.M.G.-G. and C.S. acknowledge support from the European Commission, CrowdHealth project (H2020-SC1-2016-CNECT No. 727560).Iglesias-Martinez, ME.; Garcia-Gomez, JM.; Sáez Silvestre, C.; Fernández De Córdoba, P.; Conejero, JA. (2018). Feature extraction and similarity of movement detection during sleep, based on higher order spectra and entropy of the actigraphy signal: Results of the Hispanic Community Health Study/Study of Latinos. Sensors. 18(12):4310-1-4310-17. https://doi.org/10.3390/s18124310S4310-14310-17181

miR-146a is a pivotal regulator of neutrophil extracellular trap formation promoting thrombosis.

Neutrophil extracellular traps (NETs) induce a procoagulant response linking inflammation and thrombosis. Low levels of miR-146a, a brake of inflammatory response, are involved in higher risk for cardiovascular events, but the mechanisms explaining how miR-146a exerts its function remain largely undefined. The aim of this study was to explore the impact of miR-146a deficiency in NETosis both, in sterile and non-sterile models in vivo, and to inquire into the underlying mechanism. Two models of inflammation were performed: 1) Ldlr-/- mice transplanted with bone marrow from miR-146a-/- or wild type (WT) were fed high-fat diet, generating an atherosclerosis model; and 2) an acute inflammation model was generated by injecting lipopolysaccharide (LPS) (1 mg/Kg) into miR-146a-/- and WT mice. miR-146a deficiency increased NETosis in both models. Accordingly, miR-146a-/- mice showed significant reduced carotid occlusion time and elevated levels of NETs in thrombi following FeCl3-induced thrombosis. Infusion of DNAse I abolished arterial thrombosis in WT and miR-146a-/- mice. Interestingly, miR-146a deficient mice have aged, hyperreactive and pro-inflammatory neutrophils in circulation that are more prone to form NETs independently of the stimulus. Furthermore, we demonstrated that community acquired pneumonia (CAP) patients with reduced miR-146a levels associated with the T variant of the functional rs2431697, presented an increased risk for cardiovascular events due in part to an increased generation of NETs.This work was supported by research grants from Instituto de Salud Carlos III (ISCIII), Fondo Europeo de Desarrollo Regional “Investing in your future” (PI17/00051 y PI17/01421) (PFIS18/0045: A.M. de los Reyes-García) (CD18/00044: S. Águila), and Fundación Séneca (19873/GERM/15). The CNIC is supported by the ISCIII, the Ministerio de Ciencia, Innovación y Universidades (MCIU), and the Fundación Pro CNIC, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). A.B. Arroyo has a research fellowship from Sociedad Española de Trombosis y Hemostasia (SETH). The MCIU supported A.dM. (predoctoral contract BES-2014-067791).S

Atmospheric water triggers supramolecular gel formation of novel low molecular weight maslinic and oleanolic triterpenic derivatives

Pentacyclic triterpenes have a rigid lipophilic backbone decorated with polar functional groups such as hydroxyl, carbonyl and carboxyl, which make them attractive natural amphiphiles. The ability of this type of compound to self-assemble into complex nanostructures has recently gained interest due in part to the abundant existence of renewable feedstocks. Herein, we present two new maslinic and oleanolic triterpene pentacyclic derivatives that have the ability to self-assemble into long fibers giving rise to homogeneous gels. Quite remarkably, these molecules are able to form gels by slowly capturing atmospheric water from their DMSO and DMF solutions. To the best of our knowledge, this mechanism of gel formation has not been previously reported for other LMWGs and highlights the versatility of these compounds to form gels as a response to different external stimuli. The micro- and macroscopic properties of the resulting gels have been studied in detail by TEM, SEM, NMR, VCD, FTIR, XRD and rheology. We have demonstrated that gels prepared by capturing atmospheric water in DMSO are more homogeneous and stiffer than those obtained by direct addition of water to the organic solution.Departamento de Química Orgánic

Involvement of stanniocalcins in the deregulation of glycaemia in obese mice and type 2 diabetic patients

Las estanniocalcinas se expresan en el tejido del páncreas, y se sugirió una correlación directa entre la insulina circulante y las concentraciones de STC2 en el ser humano. Aquí, mostramos una correlación significativa entre STC1 y tanto la glucemia como la hemoglobina glicosilada entre los pacientes con DM2, mientras que los pacientes con DM2 que presentan los mayores valores de hemoglobina glicosilada exhibieron la menor expresión de STC2. Sin embargo, el tratamiento de los pacientes con fármacos antiglicémicos no modifica significativamente la expresión de ambas STC. Por otra parte, los ratones STC2-/- que mostraron sobrepeso neonatal y adulto presentaron además una glucemia desregulada cuando fueron alimentados con una dieta hipercalórica (pellet de cría, BP). Esta alteración es más evidente en las primeras etapas de la vida animal. La glucemia desregulada en estos ratones se confirmó mediante una prueba oral de glucosa. Además, los ratones STC2-/- presentan un aumento del tamaño del páncreas; así, el análisis histológico revela que los ratones WT responden a la dieta BP aumentando el tamaño de los islotes pancreáticos a través de la inducción de la división celular, y los ratones STC2-/- carecen de este mecanismo compensatorio. Contrariamente, los ratones alimentados con STC2-/- muestran un mayor número de islotes pero de tamaño similar a los alimentados con el pellet regular. El análisis histopatológico demuestra la alteración de la estructura de los tejidos y las infiltraciones de eritrocitos en los ratones STC2-/-, posiblemente debido al estrés evocado por la dieta BP. Por último, se observó una mayor inmunotinción de glucagón en el islote de los ratones STC2-/-, y el ensayo ELISA de glucagón confirmó el aumento del glucagón circulante. En resumen, presentamos pruebas del papel de los STC, principalmente el STC2, como posible marcador temprano durante el desarrollo de la diabetes mellitus.Stanniocalcins are expressed in the pancreas tissue, and it was suggested a direct correlation between circulating insulin and STC2 concentrations in human. Here, we show a significant correlation between STC1 and both glycaemia and glycosylated haemoglobin among DM2 patients, while DM2 patients who present the greatest glycosylated haemoglobin values exhibited the lowest STC2 expression. However, treatment of patients with antiglycaemic drugs does not significantly modify the expression of both STCs. On the other hand, STC2-/- mice that exhibited neonatal and adult overweight further presented deregulated glycaemia when they were feed with a hypercaloric diet (breeding pellet, BP). This alteration is more evident at the early stages of the animal life. Deregulated glycaemia in these mice was confirmed using glucose oral test. In addition, STC2-/- mice present enhanced pancreas size; thus, the histological analysis reveals that WT mice respond to BP diet by increasing the size of the pancreatic islets through inducing cell division, and STC2-/- mice lack this compensatory mechanism. Contrary, BP fed STC2-/- mice show enhanced number of islets but of similar size than those fed with regular pellet. Histopathological analysis demonstrates tissue structure disruption and erythrocytes infiltrations in STC2-/- mice, possibly due to the stress evoked by the BP diet. Finally, enhanced glucagon immunostaining was observed in the islet of STC2-/- mice, and the glucagon ELISA assay confirmed the increase in the circulating glucagon. Summarizing, we present evidence of the role of STCs, mainly STC2, as a possible early marker during development of diabetes mellitus.• Ministerio de Economía y Competitividad. Becas 2013‐45564C2‐1‐P, BFU‐2016‐74932‐C2‐1‐P • Programa Juan de la Cierva. Becas IJCI‐2015‐25665, JC‐2012‐ 2934 • Junta de Extremadura. Beca PRIIB16046peerReviewe

miR-146a rs2431697 identifies myeloproliferative neoplasm patients with higher secondary myelofibrosis progression risk

Myelofibrosis (MF) occurs as part of the natural history of polycythemia vera (PV) and essential thrombocythemia (ET), and remarkably shortens survival. Although JAK2V617F and CALR allele burden are the main transformation risk factors, inflammation plays a critical role by driving clonal expansion toward end-stage disease. NF-κB is a key mediator of inflammation-induced carcinogenesis. Here, we explored the involvement of miR-146a, a brake in NF-κB signaling, in MPN susceptibility and progression. rs2910164 and rs2431697, that affect miR-146a expression, were analyzed in 967 MPN (320 PV/333 ET/314 MF) patients and 600 controls. We found that rs2431697 TT genotype was associated with MF, particularly with post-PV/ET MF (HR = 1.5; p < 0.05). Among 232 PV/ET patients (follow-up time=8.5 years), 18 (7.8%) progressed to MF, being MF-free-survival shorter for rs2431697 TT than CC + CT patients (p = 0.01). Multivariate analysis identified TT genotype as independent predictor of MF progression. In addition, TT (vs. CC + CT) patients showed increased plasma inflammatory cytokines. Finally, miR-146a−/− mice showed significantly higher Stat3 activity with aging, parallel to the development of the MF-like phenotype. In conclusion, we demonstrated that rs2431697 TT genotype is an early predictor of MF progression independent of the JAK2V617F allele burden. Low levels of miR-146a contribute to the MF phenotype by increasing Stat3 signaling

In praise of arrays

Microarray technologies have both fascinated and frustrated the transplant community since their introduction roughly a decade ago. Fascination arose from the possibility offered by the technology to gain a profound insight into the cellular response to immunogenic injury and the potential that this genomic signature would be indicative of the biological mechanism by which that stress was induced. Frustrations have arisen primarily from technical factors such as data variance, the requirement for the application of advanced statistical and mathematical analyses, and difficulties associated with actually recognizing signature gene-expression patterns and discerning mechanisms. To aid the understanding of this powerful tool, its versatility, and how it is dramatically changing the molecular approach to biomedical and clinical research, this teaching review describes the technology and its applications, as well as the limitations and evolution of microarrays, in the field of organ transplantation. Finally, it calls upon the attention of the transplant community to integrate into multidisciplinary teams, to take advantage of this technology and its expanding applications in unraveling the complex injury circuits that currently limit transplant survival

Final results from the PERUSE study of first-line pertuzumab plus trastuzumab plus a taxane for HER2-positive locally recurrent or metastatic breast cancer, with a multivariable approach to guide prognostication

Background: The phase III CLinical Evaluation Of Pertuzumab And TRAstuzumab (CLEOPATRA) trial established the combination of pertuzumab, trastuzumab and docetaxel as standard first-line therapy for human epidermal growth factor receptor 2 (HER2)-positive locally recurrent/metastatic breast cancer (LR/mBC). The multicentre single-arm PERtUzumab global SafEty (PERUSE) study assessed the safety and efficacy of pertuzumab and trastuzumab combined with investigator-selected taxane in this setting. Patients and methods: Eligible patients with inoperable HER2-positive LR/mBC and no prior systemic therapy for LR/mBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab and pertuzumab until disease progression or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Prespecified subgroup analyses included subgroups according to taxane, hormone receptor (HR) status and prior trastuzumab. Exploratory univariable analyses identified potential prognostic factors; those that remained significant in multivariable analysis were used to analyse PFS and OS in subgroups with all, some or none of these factors. Results: Of 1436 treated patients, 588 (41%) initially received paclitaxel and 918 (64%) had HR-positive disease. The most common grade 653 adverse events were neutropenia (10%, mainly with docetaxel) and diarrhoea (8%). At the final analysis (median follow-up: 5.7 years), median PFS was 20.7 [95% confidence interval (CI) 18.9-23.1] months overall and was similar irrespective of HR status or taxane. Median OS was 65.3 (95% CI 60.9-70.9) months overall. OS was similar regardless of taxane backbone but was more favourable in patients with HR-positive than HR-negative LR/mBC. In exploratory analyses, trastuzumab-pretreated patients with visceral disease had the shortest median PFS (13.1 months) and OS (46.3 months). Conclusions: Mature results from PERUSE show a safety and efficacy profile consistent with results from CLEOPATRA and median OS exceeding 5 years. Results suggest that paclitaxel is a valid alternative to docetaxel as backbone chemotherapy. Exploratory analyses suggest risk factors that could guide future trial design